Malaria and iron deficiency frequently coexist in African children. Both conditions are major causes of anemia and cognitive impairment. However, treatment of iron deficiency in children with malaria is problematic. Iron is essential for P. falciparum survival. Iron therapy at the time of malaria treatment may lead to delayed parasite clearance and an increased risk of subsequent malaria. Conversely, malaria- induced inflammation leads to changes in iron metabolism (reduced intestinal iron absorption, iron trapping in the reticuloendothelial system) that can persist for >2 weeks, potentially reducing the efficacy of oral iron supplements^'^. Several studies suggest that sequestering of iron is an important component in the pathophysiology of malarial anemia, but few have assessed the effect that iron sequestration has on the developing brain. We have an ongoing study (5R01NS055349) on the pathogenesis of cognitive impairment in a cohort of Ugandan children with severe malaria. Within this malaria cohort, we propose in the present study to evaluate the effects of immediate vs. delayed treatment of iron deficiency on short and long-term iron status (Aim 1), risk of subsequent malaria (Aim 2), and long-term neurobehavioral function (Aim 3), and to identify potential mechanisms that mediate these effects. In Aim 1, children with severe malaria who are iron-deficient will be randomized to receive immediate or 1-month-delayed iron treatment. Hemoglobin, iron status (ZnPP, ferritin, TfR), erythropoiesis (erythropoietin, reticulocyte count) and inflammation (hepcidin, ferritin, alphal-acid glycoprotein, cytokines) will then be measured at baseline and 1, 6 and 12 months later and compared between treatment groups. In Aim 2, cctive surveillance for malaria episodes will be performed, and number of malaria episodes will be compared in children with immediate vs. delayed iron treatment over the 1-year period of follow-up. In Aim 3, evaluation of behaviors specifically affected by iron deficiency will be added to the detailed cognitive testing administered in the current study at enrollment and 6 and 12 months later. The CSF proteome in children with cerebral malaria will also be compared in those with and without iron deficiency. We expect that this study will constitute a major advance in our understanding of how malaria-iron interactions influence anemia, malaria risk and neurobehavioral development in children, and will provide a foundation for future large-scale iron supplementation trials in malaria endemic areas. PUBLIC HEALTH RELEVANCE: Malaria and iron deficiency frequently coexist in African children and are major causes of anemia and cognitive impairment. The present study will assess whether delaying iron treatment until after malaria- related inflammation is reduced leads to improved iron status, hemoglobin level and cognitive and behavioral outcomes in children in Africa. Information from this study will guide future iron and malaria intervention programs in Africa.